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BACKGROUND: Positive effects of RNS60 on respiratory and bulbar function were observed in a phase 2 randomized, placebo-controlled trial in people with amyotrophic lateral sclerosis (ALS). OBJECTIVE: to investigate the long-term survival of trial participants and its association with respiratory status and biomarkers of neurodegeneration and inflammation. STUDY DESIGN AND SETTINGS: A randomized, double blind, phase 2 clinical trial was conducted. Trial participants were enrolled at 22 Italian Expert ALS Centres from May 2017 to January 2020. Vital status of all participants was ascertained thirty-three months after the trial's last patient last visit (LPLV). Participants were patients with Amyotrophic Lateral Sclerosis, classified as slow or fast progressors based on forced vital capacity (FVC) slope during trial treatment. Demographic, clinical, and biomarker levels and their association with survival were also evaluated. RESULTS: Mean duration of follow-up was 2.8 years. Long-term median survival was six months longer in the RNS60 group (p = 0.0519). Baseline FVC, and rates of FVC decline during the first 4 weeks of trial participation, were balanced between the active and placebo treatment arms. After 6 months of randomized, placebo-controlled treatment, FVC decline was significantly slower in the RNS60 group compared to the placebo group. Rates of FVC progression during the treatment were strongly associated with long-term survival (median survival: 3.7 years in slow FVC progressors; 1.6 years in fast FVC progressors). The effect of RNS60 in prolonging long-term survival was higher in participants with low neurofilament light chain (NfL) (median survival: >4 years in low NfL - RNS60 group; 3.3 years in low NfL - placebo group; 1.9 years in high NfL - RNS60 group; 1.8 years in high NfL - placebo group) and Monocyte Chemoattractant Protein-1 (MCP-1) (median survival: 3.7 years in low MCP-1 - RNS60 group; 2.3 years in low MCP-1 - placebo group; 2.8 years in high MCP-1 - RNS60 group; 2.6 years in high MCP-1 - placebo group) levels at baseline. CONCLUSIONS AND RELEVANCE: In this post-hoc analysis, long term survival was longer in participants randomized to RNS60 compared with those randomized to placebo and was correlated with slower FVC progression rates, suggesting that longer survival may be mediated by the drug's effect on respiratory function. In these post-hoc analyses, the beneficial effect of RNS60 on survival was most pronounced in participants with low NfL and MCP-1 levels at study entry, suggesting that this could be a subgroup to target in future studies investigating the effects of RNS60 on survival. TRIAL REGISTRATION: Study preregistered on 13/Jan/2017 in EUDRA-CT (2016-002382-62). The study was also registered at ClinicalTrials.gov number NCT03456882.
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BACKGROUND: SerpinA1, a serine protease inhibitor, is involved in the modulation of microglial-mediated inflammation in neurodegenerative diseases. We explored SerpinA1 levels in cerebrospinal fluid (CSF) and serum of amyotrophic lateral sclerosis (ALS) patients to understand its potential role in the pathogenesis of the disease. METHODS: SerpinA1, neurofilament light (NfL) and heavy (NfH) chain, and chitinase-3-like protein-1 (CHI3L1) were determined in CSF and serum of ALS patients (n = 110) and healthy controls (n = 10) (automated next-generation ELISA), and correlated with clinical parameters, after identifying three classes of progressors (fast, intermediate, slow). Biomarker levels were analyzed for diagnostic power and association with progression and survival. RESULTS: SerpinA1serum was significantly decreased in ALS (median: 1032 µg/mL) compared with controls (1343 µg/mL) (p = 0.02). SerpinA1CSF was elevated only in fast progressors (8.6 µg/mL) compared with slow (4.43 µg/mL, p = 0.01) and intermediate (4.42 µg/mL, p = 0.03) progressors. Moreover, SerpinA1CSF correlated with neurofilament and CHI3L1 levels in CSF. Contrarily to SerpinA1CSF , neurofilament and CHI3L1 concentrations in CSF correlated with measures of disease progression in ALS, while SerpinA1serum mildly related with time to generalization (rho = 0.20, p = 0.04). In multivariate analysis, the ratio between serum and CSF SerpinA1 (SerpinA1 ratio) and NfHCSF were independently associated with survival. CONCLUSIONS: Higher SerpinA1CSF levels are found in fast progressors, suggesting SerpinA1 is a component of the neuroinflammatory mechanisms acting upon fast-progressing forms of ALS. Both neurofilaments or CHI3L1CSF levels outperformed SerpinA1 at predicting disease progression rate in our cohort, and so the prognostic value of SerpinA1 alone as a measure remains inconclusive.
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Esclerosis Amiotrófica Lateral , Humanos , Esclerosis Amiotrófica Lateral/diagnóstico , Progresión de la Enfermedad , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Pronóstico , BiomarcadoresRESUMEN
Neuropsychiatric disorders are anticipated to be a leading health concern in the near future, emphasizing an outstanding need for the development of new effective therapeutics to treat them. Stilbenes, with resveratrol attracting the most attention, are an example of multi-target compounds with promising therapeutic potential for a broad array of neuropsychiatric and neurological conditions. This review is a comprehensive summary of the current state of research on stilbenes in several neuropsychiatric and neurological disorders such as depression, anxiety, schizophrenia, autism spectrum disorders, epilepsy, traumatic brain injury, and neurodegenerative disorders. We describe and discuss the results of both in vitro and in vivo studies. The majority of studies concentrate on resveratrol, with limited findings exploring other stilbenes such as pterostilbene, piceatannol, polydatin, tetrahydroxystilbene glucoside, or synthetic resveratrol derivatives. Overall, although extensive preclinical studies show the potential benefits of stilbenes in various central nervous system disorders, clinical evidence on their therapeutic efficacy is largely missing.
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Lesiones Traumáticas del Encéfalo , Enfermedades Neurodegenerativas , Estilbenos , Humanos , Resveratrol , Enfermedades Neurodegenerativas/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/tratamiento farmacológicoRESUMEN
Stress granules (SGs) are dynamic condensates associated with protein misfolding diseases. They sequester stalled mRNAs and signaling factors, such as the mTORC1 subunit raptor, suggesting that SGs coordinate cell growth during and after stress. However, the molecular mechanisms linking SG dynamics and signaling remain undefined. We report that the chaperone Hsp90 is required for SG dissolution. Hsp90 binds and stabilizes the dual-specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3) in the cytosol. Upon Hsp90 inhibition, DYRK3 dissociates from Hsp90 and becomes inactive. Inactive DYRK3 is subjected to two different fates: it either partitions into SGs, where it is protected from irreversible aggregation, or it is degraded. In the presence of Hsp90, DYRK3 is active and promotes SG disassembly, restoring mTORC1 signaling and translation. Thus, Hsp90 links stress adaptation and cell growth by regulating the activity of a key kinase involved in condensate disassembly and translation restoration.
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Gránulos Citoplasmáticos , Transducción de Señal , Citoplasma , Gránulos Citoplasmáticos/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Fosforilación , ARN Mensajero/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. RNS60 is an immunomodulatory and neuroprotective investigational product that has shown efficacy in animal models of ALS and other neurodegenerative diseases. Its administration has been safe and well tolerated in ALS subjects in previous early phase trials. METHODS: This was a phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial. Participants diagnosed with definite, probable or probable laboratory-supported ALS were assigned to receive RNS60 or placebo administered for 24 weeks intravenously (375 ml) once a week and via nebulization (4 ml/day) on non-infusion days, followed by an additional 24 weeks off-treatment. The primary objective was to measure the effects of RNS60 treatment on selected biomarkers of inflammation and neurodegeneration in peripheral blood. Secondary objectives were to measure the effect of RNS60 on functional impairment (ALS Functional Rating Scale-Revised), a measure of self-sufficiency, respiratory function (forced vital capacity, FVC), quality of life (ALS Assessment Questionnaire-40, ALSAQ-40) and survival. Tolerability and safety were assessed. RESULTS: Seventy-four participants were assigned to RNS60 and 73 to placebo. Assessed biomarkers did not differ between arms. The mean rate of decline in FVC and the eating and drinking domain of ALSAQ-40 was slower in the RNS60 arm (FVC, difference 0.41 per week, standard error 0.16, p = 0.0101; ALSAQ-40, difference -0.19 per week, standard error 0.10, p = 0.0319). Adverse events were similar in the two arms. In a post hoc analysis, neurofilament light chain increased over time in bulbar onset placebo participants whilst remaining stable in those treated with RNS60. CONCLUSIONS: The positive effects of RNS60 on selected measures of respiratory and bulbar function warrant further investigation.
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Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Humanos , Esclerosis Amiotrófica Lateral/diagnóstico , Calidad de Vida , Método Doble Ciego , Biomarcadores , Resultado del TratamientoRESUMEN
Mutations in the tubulin-specific chaperon D (TBCD) gene, involved in the assembly and disassembly of the α/ß-tubulin heterodimers, have been reported in early-onset progressive neurodevelopment regression, with epilepsy and mental retardation. We describe a rare homozygous variant in TBCD, namely c.881G>A/p.Arg294Gln, in a young woman with a phenotype dominated by distal motorneuronopathy and mild mental retardation, with neuroimaging evidence of corpus callosum hypoplasia. The peculiar phenotype is discussed in light of the molecular interpretation, enriching the literature data on tubulinopathies generated from TBCD mutations.
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Epilepsia , Discapacidad Intelectual , Humanos , Proteínas Asociadas a Microtúbulos/metabolismo , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/metabolismo , Discapacidad Intelectual/genética , Tubulina (Proteína)/metabolismoRESUMEN
Recent genetic and biochemical evidence has improved our understanding of the pathomechanisms that lead to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative diseases with overlapping symptoms and causes. Impaired RNA metabolism, enhanced aggregation of protein-RNA complexes, aberrant formation of ribonucleoprotein (RNP) granules and dysfunctional protein clearance via autophagy are emerging as crucial events in ALS/FTD pathogenesis. Importantly, these processes interact at the molecular level, converging on a common pathogenic cascade. In this review, we summarize key principles underlying ALS and FTD, and we discuss how mutations in genes involved in RNA metabolism, protein quality control and protein degradation meet mechanistically to impair the functionality and dynamics of RNP granules, and how this leads to cellular toxicity and death. Finally, we describe recent advances in understanding signaling pathways that become dysfunctional in ALS/FTD, partly due to altered RNP granule dynamics, but also with stress granule-independent mechanisms and, thus could be promising targets for future therapeutic intervention.
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Esclerosis Amiotrófica Lateral/metabolismo , Demencia Frontotemporal/metabolismo , Proteínas de Unión al ARN/metabolismo , ARN/metabolismo , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Humanos , ARN/genética , Proteínas de Unión al ARN/genéticaRESUMEN
Biomarkers of neuronal damage in status epilepticus (SE) would be of great relevance for clinical and research purposes. In a retrospective cross-sectional study, serum neurofilament light chain (NfL) levels were measured in patients with SE (30 subjects), patients with drug-resistant epilepsy (30 subjects), and healthy controls (30 subjects). Serum NfL levels were higher in patients with SE (median = 26.15 pg/ml) compared to both epilepsy patients (median = 7.35 pg/ml) and healthy controls (median = 6.81 pg/ml; p < .001). In patients with SE, serum NfL levels showed a high correlation with cerebrospinal fluid (CSF) NfL (τ = .68, p < .001) as well as with CSF total tau (t-tau) levels (τ = .627, p < .001); they were higher in SE lasting >24 h (p = .013), in refractory/superrefractory SE (p = .004), and in patients who died within 30 days or who presented a worsening of clinical conditions (p = .001). Values of >28.8 pg/ml predicted 30-day clinical worsening or death (odds ratio [OR] = 10.83, 95% confidence interval [CI] = 1.96-59.83, p = .006) and SE refractoriness (OR = 9.33, 95% CI = 1.51-57.65, p = .016). In conclusion, serum NfL levels are increased in SE and correlate with SE treatment response, duration, and outcomes, therefore representing a promising biomarker of seizure-related neuronal damage.
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Filamentos Intermedios , Estado Epiléptico , Biomarcadores , Estudios Transversales , Humanos , Proteínas de Neurofilamentos , Estudios Retrospectivos , ConvulsionesRESUMEN
Strong evidence suggests that endoplasmic reticulum stress plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through altered regulation of proteostasis. Robust preclinical findings demonstrated that guanabenz selectively inhibits endoplasmic reticulum stress-induced eIF2α-phosphatase, allowing misfolded protein clearance, reduces neuronal death and prolongs survival in in vitro and in vivo models. However, its safety and efficacy in patients with ALS are unknown. To address these issues, we conducted a multicentre, randomized, double-blind trial with a futility design. Patients with ALS who had displayed an onset of symptoms within the previous 18 months were randomly assigned in a 1:1:1:1 ratio to receive 64 mg, 32 mg or 16 mg of guanabenz or placebo daily for 6 months as an add-on therapy to riluzole. The purpose of the placebo group blinding was to determine safety but not efficacy. The primary outcome was the proportion of patients progressing to higher stages of disease within 6 months as measured using the ALS Milano-Torino staging system, compared with a historical cohort of 200 patients with ALS. The secondary outcomes were the rate of decline in the total revised ALS functional rating scale score, slow vital capacity change, time to death, tracheotomy or permanent ventilation and serum light neurofilament level at 6 months. The primary assessment of efficacy was performed using intention-to-treat analysis. The treatment arms using 64 mg and 32 mg guanabenz, both alone and combined, reached the primary hypothesis of non-futility, with the proportions of patients who progressed to higher stages of disease at 6 months being significantly lower than that expected under the hypothesis of non-futility and a significantly lower difference in the median rate of change in the total revised ALS functional rating scale score. This effect was driven by patients with bulbar onset, none of whom (0/18) progressed to a higher stage of disease at 6 months compared with those on 16 mg guanabenz (4/8; 50%), the historical cohort alone (21/49; 43%; P = 0.001) or plus placebo (25/60; 42%; P = 0.001). The proportion of patients who experienced at least one adverse event was higher in any guanabenz arm than in the placebo arm, with higher dosing arms having a significantly higher proportion of drug-related side effects and the 64 mg arm a significantly higher drop-out rate. The number of serious adverse events did not significantly differ between the guanabenz arms and the placebo. Our findings indicate that a larger trial with a molecule targeting the unfolded protein response pathway without the alpha-2 adrenergic related side-effect profile of guanabenz is warranted.
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Agonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/metabolismo , Guanabenzo/uso terapéutico , Respuesta de Proteína Desplegada/fisiología , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Anciano , Esclerosis Amiotrófica Lateral/diagnóstico , Método Doble Ciego , Femenino , Guanabenzo/farmacología , Humanos , Masculino , Persona de Mediana Edad , Respuesta de Proteína Desplegada/efectos de los fármacosRESUMEN
Mutations in Matrin-3 (MATR3) gene have been described in ALS, suggesting a role for this gene in the disease pathogenesis. While most of MATR3 mutations are point mutations, here we report the first case of ALS associated with duplication in exons 15 and 16. The patient presented with limb-onset ALS and a complex past medical history because of Sjögren syndrome, antiphospholipid antibodies positivity, polyallergies, endometriosis, aldosterone-secreting adrenal cortical adenoma, congenital vesicoureteral reflux, and right breast hypoplasia. We discuss MATR3 effect in ALS and the role of this previously undescribed mutation in this peculiar ALS phenotype associated with systemic autoimmunity involvement.
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Esclerosis Amiotrófica Lateral , Esclerosis Amiotrófica Lateral/genética , Exones/genética , Femenino , Humanos , Mutación/genética , Proteínas Asociadas a Matriz Nuclear , Fenotipo , Proteínas de Unión al ARNRESUMEN
BACKGROUND: ALS symptoms have been previously described only in the context of ATXN2 CAG expansions, whereas missense mutations of the gene have never been described in ALS patients. CASE PRESENTATION: We identified a novel missense mutation (c.2860C > T) of ATXN2, for which in silico analysis showed a possible pathogenic effect on protein expression, in a patient presenting an aggressive disease phenotype. DISCUSSION: Our findings raise the possibility for unknown genetic factors interacting with ATXN2 mutations, or for an autonomous pathogenic role for this specific point mutation in ATXN2 gene in driving the clinical phenotype toward ALS. We also found that stress granules in the fibroblasts from the patient entrapped higher amounts of defective ribosomal products compared to fibroblasts from three healthy subjects, suggesting that ATXN2 mutation-related toxicity may have implication in protein quality control.
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Esclerosis Amiotrófica Lateral , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Ataxina-2/genética , Humanos , Mutación , Mutación Missense , Fenotipo , Proteínas/genética , Expansión de Repetición de TrinucleótidoRESUMEN
BACKGROUND: Dysphagia is a common symptom during the trajectory of ALS, and it can significantly impact on the quality of life and prognosis of patients. Nowadays, no specific tool for the screening of dysphagia in ALS is validated, and the approach is heterogeneous across the Italian centres. OBJECTIVE: To validate the DYALS (dysphagia in amyotrophic lateral sclerosis) questionnaire, adapting the DYMUS (dysphagia in multiple sclerosis) questionnaire, for the assessment of dysphagia in ALS patients, in order to uniform the evaluations across the Italian ALS network. METHODS: We included 197 patients diagnosed with ALS following the El Escorial criteria, in sixteen Italian ALS centres between 1st December 2019 and 1st July 2020. For each patient, we collected clinical and demographic data and obtained ALSFRS-r score, ALSAQ-5 score, DYMUS score, and EAT-10 score. RESULTS: Across the 197 patients, the ratio M/F was 113/84, and the median age was 64 years (IQR 56-72.5). Bulbar patients were 20%, and spinal patients 80%. The median ALSFRSr total score of patients was 35 (IQR 28-39). DYALS score was statistically higher in bulbar ALS than in spinal ALS (median = 6, IQR 4.5-9 vs median = 1, IQR 0-5, z = 6.253, p < 0.0001). DYALS questionnaire showed a high internal consistency (Cronbach's alpha = 0.88). There was a statistically significant correlation between DYALS and EAT-10 (rho = 0.90, p < 0.0001). CONCLUSIONS: DYALS scale is reliable, manageable, and easily usable for the screening of dysphagia in ALS. It can be shared with all the Italian ALS centres in order to collect uniform data for therapeutic strategies and clinical trials.
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Esclerosis Amiotrófica Lateral , Trastornos de Deglución , Esclerosis Múltiple , Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/diagnóstico , Trastornos de Deglución/diagnóstico , Trastornos de Deglución/etiología , Humanos , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico , Calidad de Vida , Encuestas y CuestionariosRESUMEN
Gut microbiota is a complex ecosystem composed by trillions of microorganisms that are crucial for human health or disease status. Currently, there are two methodological options to explore its complexity: metagenomics and culturomics. Culturomics is an approach that uses multiple culture conditions (days of incubation, enrichment factors and growth temperature) and MALDI-TOF mass spectrometry for the identification of bacterial species and sequencing when this method fails. In this paper, we describe how Colturomic's protocol has allowed the first isolation in human sample of Rummeliibacillus suwonensis, a Gram positive, facultative anaerobe bacterium. The bacterium was isolated from feces of a 69 years old male with amyotrophic lateral sclerosis (ALS) recruited for a clinical trial assessing safety and efficacy of fecal microbiota transplantation in ALS. The first isolation of the microorganism dates back to 2013 from the soil of a South Korean mountain area. In this report, morphological description, biochemical characterization and antibiotic susceptibility tests were performed to outline the bacterial properties.
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Planococcaceae , Anciano , Esclerosis Amiotrófica Lateral , Heces/microbiología , Humanos , Masculino , Planococcaceae/aislamiento & purificación , ARN Ribosómico 16SRESUMEN
Amyotrophic lateral sclerosis is the most common form of motor neuron disease. Mutations in TARDBP, the gene encoding the RNA-binding protein TDP-43, are responsible for about 5% of familial ALS. Here we report the clinical and biological features of an ALS patients with pA382T mutation in TPD-43 protein. Disease began with right hand muscles weakness, and equally involved upper and lower motor neuron with a classic phenotype, without cognitive impairment. While a family history of neurological diseases was reported, there was no evidence of familial frontotemporal dementia. Cultured fibroblasts from the patient were characterized by profound alterations of cell proteome, which impacts particularly the mitochondrial metabolic pathways and the endoplasmic reticulum. TDP-43 levels were similar to control, healthy fibroblasts, but a higher fraction localized in mitochondria. Mitochondrial network appeared fragmented, and the organelles smaller and more spheric. In agreement with impaired proteome and morphology of mitochondria, basal cell respiration was reduced. Mitochondrial DNA levels appeared normal. However, a higher amount of mitochondrial DNA was present in the cytosol, suggesting a pronounced mitochondrial DNA misplacement which can promote a pro-inflammatory response mediating by cGAS/STING. Thus, this case report further expands the clinical and pathological phenotype of A382T mutation.
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Esclerosis Amiotrófica Lateral , Esclerosis Amiotrófica Lateral/metabolismo , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Retículo Endoplásmico/metabolismo , Humanos , Mitocondrias/metabolismo , Mutación , Nucleotidiltransferasas/metabolismo , Proteoma/metabolismo , Proteínas de Unión al ARN/metabolismoRESUMEN
Selenoprotein P, a selenium-transporter protein, has been hypothesized to play a role in the etiology of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's dementia (AD). However, data in humans are scarce and largely confined to autoptic samples. In this case-control study, we determined selenoprotein P concentrations in both the cerebrospinal fluid (CSF) and the serum of 50 individuals diagnosed with ALS, 30 with AD, 54 with mild cognitive impairment (MCI) and of 30 controls, using sandwich enzyme-linked immunosorbent assay (ELISA) methods. We found a positive and generally linear association between CSF and serum selenoprotein P concentrations in all groups. CSF selenoprotein P and biomarkers of neurodegeneration were positively associated in AD, while for MCI, we found an inverted-U-shaped relation. CSF selenoprotein P concentrations were higher in AD and MCI than in ALS and controls, while in serum, the highest concentrations were found in MCI and ALS. Logistic and cubic spline regression analyses showed an inverse association between CSF selenoprotein P levels and ALS risk, and a positive association for AD risk, while an inverted-U-shaped relation with MCI risk emerged. Conversely, serum selenoprotein P concentrations were positively associated with risk of all conditions but only in their lower range. Overall, these findings indicate some abnormalities of selenoprotein P concentrations in both the central nervous system and blood associated with ALS and neurocognitive disorders, though in different directions. These alterations may reflect either phenomena of etiologic relevance or disease-induced alterations of nutritional and metabolic status.
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Enfermedad de Alzheimer , Esclerosis Amiotrófica Lateral , Disfunción Cognitiva , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Esclerosis Amiotrófica Lateral/diagnóstico , Biomarcadores/líquido cefalorraquídeo , Estudios de Casos y Controles , Disfunción Cognitiva/líquido cefalorraquídeo , Humanos , Fragmentos de Péptidos/líquido cefalorraquídeo , Selenoproteína P , Proteínas tau/líquido cefalorraquídeoRESUMEN
BACKGROUND: More than 30 causative genes have been identified in familial and sporadic amyotrophic lateral sclerosis (ALS). The next-generation sequencing (NGS) is a powerful and groundbreaking tool to identify disease-associated variants. Despite documented advantages of NGS, its diagnostic reliability needs to be addressed in order to use this technology for specific routine diagnosis. MATERIAL AND METHODS: Literature database was explored to identify studies comparing NGS and Sanger sequencing for the detection of variants causing ALS. We collected data about patients' characteristics, disease type and duration, NGS and Sanger properties. RESULTS: More than 200 bibliographic references were identified, of which only 14 studies matching our inclusion criteria. Only 2 out of 14 studies compared results of NGS analysis with the Sanger sequencing. Twelve studies screened causative genes associated to ALS using NGS technologies and confirmed the identified variants with Sanger sequencing. Overall, data about more 2,000 patients were analysed. The number of genes that were investigated in each study ranged from 1 to 32, the most frequent being FUS, OPTN, SETX and VCP. NGS identified already known mutations in 21 genes, and new or rare variants in 27 genes. CONCLUSIONS: NGS seems to be a promising tool for the diagnosis of ALS in routine clinical practice. Its advantages are represented by an increased speed and a lowest sequencing cost, but patients' counselling could be problematic due to the discovery of frequent variants of unknown significance.
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Esclerosis Amiotrófica Lateral/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Análisis de Secuencia de ADN , Proteínas de Ciclo Celular/genética , ADN Helicasas/genética , Humanos , Proteínas de Transporte de Membrana/genética , Enzimas Multifuncionales/genética , ARN Helicasas/genética , Proteína FUS de Unión a ARN/genética , Reproducibilidad de los Resultados , Proteína que Contiene Valosina/genéticaRESUMEN
BACKGROUND: Epidemiological studies highlighted the possibility that exposure to cyanotoxins leads to the development of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). METHODS: We devised a population-based case-control study in two Italian populations. We used residential proximity of the residence to water bodies as a measure of possible exposure to cyanotoxins. RESULTS: Based on 703 newly-diagnosed ALS cases and 2737 controls, we calculated an ALS odds ratio (OR) of 1.41 (95% CI: 0.72-2.74) for current residence in the vicinity of water bodies, and a slightly lower estimate for historical residence (OR: 1.31; 95% CI: 0.57-2.99). Subjects <65 years and people living in the Northern Italy province of Modena had higher ORs, especially when historical residence was considered. CONCLUSIONS: Overall, despite some risk of bias due to exposure misclassification and unmeasured confounding, our results appear to support the hypothesis that cyanotoxin exposure may increase ALS risk.
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Esclerosis Amiotrófica Lateral , Cianobacterias , Enfermedades Neurodegenerativas , Esclerosis Amiotrófica Lateral/inducido químicamente , Esclerosis Amiotrófica Lateral/epidemiología , Estudios de Casos y Controles , Humanos , Italia/epidemiología , Factores de RiesgoRESUMEN
Autosomal dominant spinocerebellar ataxia (SCA) type 12 is a rare SCA characterized by a heterogeneous phenotype. Action tremor of the upper limbs is the most common presenting sign and cerebellar signs can appear subsequently. In many cases, minor signs, like dystonia, can be predominant even at onset. Laryngeal dystonia (spasmodic dysphonia) has been observed only in one case of SCA12 and never reported at disease onset. We present a 61-year-old female who developed spasmodic dysphonia followed by dystonic tremor and subsequent ataxia diagnosed with SCA12. Thus, spasmodic dysphonia can be a presenting symptom of SCA12.
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Disfonía/diagnóstico , Trastornos Distónicos/diagnóstico , Ataxias Espinocerebelosas/diagnóstico , Alelos , Encéfalo/diagnóstico por imagen , Femenino , Trastornos Neurológicos de la Marcha/genética , Heterocigoto , Humanos , Enfermedades de la Laringe/diagnóstico , Imagen por Resonancia Magnética , Persona de Mediana Edad , Fenotipo , TemblorRESUMEN
Some studies have reported an association between overexposure to selenium and risk of amyotrophic lateral sclerosis (ALS), a rare degenerative disease of motor neurons. From 1986 through 2015, we followed a cohort in Northern Italy that had been inadvertently consuming tap water with unusually high concentrations of inorganic hexavalent selenium from 1974 to 1985. We had previously documented an excess incidence of ALS in this cohort during 1986-1994. Here, we report extended follow-up of the cohort for an additional 21 years, encompassing 50,100 person-years of the exposed cohort and 2,233,963 person-years of the unexposed municipal cohort. We identified 7 and 112 incident ALS cases in the exposed and unexposed cohorts, respectively, yielding crude incidence rates of 14 and 5 cases per 100,000 person-years. A Poisson regression analysis, adjusting for age, sex and calendar year, produced an overall incidence rate ratio (IRR) for ALS of 2.8 (95% confidence interval (CI) 1.3, 6), with a substantially stronger IRR in 1986-1994 (8.2, 95% CI 2.7, 24.7) than in 1995-2015 (1.5, 95% CI 0.5, 4.7), and among women (5.1, 95% CI 1.8, 14.3) than men (1.7, 95% CI 0.5, 5.4). Overall, these results indicate an association between high exposure to inorganic selenium, a recognized neurotoxicant, and ALS incidence, with declining rates after cessation of exposure and stronger effects among women.
Asunto(s)
Esclerosis Amiotrófica Lateral/epidemiología , Exposición Dietética/estadística & datos numéricos , Agua Potable/química , Selenio/análisis , Contaminantes Químicos del Agua/análisis , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Italia/epidemiología , MasculinoRESUMEN
BACKGROUND: Diaphragmatic assessment by ultrasound (US) is a non-invasive and useful method in the clinical management of patients with Amyotrophic Lateral Sclerosis (ALS). The aim of our observational study was to evaluate the impact of serial assessment of the diaphragmatic function by US on long-term outcomes in a series of patients suffering from ALS and to correlate US indices of diaphragmatic function and respiratory function tests with these outcomes. METHODS: A cohort of 39 consecutive patients has been followed up to 24 months. Both lung volume (forced vital capacity, FVC) and diaphragmatic pressure generating capacity (by sniff inspiratory nasal pressure (SNIP) and by both US thickening fraction, ΔTdi, and the ratio of the thickening fraction between tidal volume and maximal lung capacity, ΔTmax) were recorded at baseline and every 3 months. Parameters were then correlated with outcomes (nocturnal hypoventilation, daily hypercapnia, start of ventilatory support (NIV), and death at 1 year) over time. RESULTS: The occurrence of ΔTmax > 0.75 increased the risk to start NIV (HR = 5.6, p = 0.001) and to die (HR = 3.7, p = 0.0001) compared with patients maintaining lower values. Moreover, compared with the occurrence of FVC < 50% of predicted, ΔTmax > 0.75 appeared slightly better correlated with NIV commencement within 6 months. CONCLUSIONS: Serial diaphragmatic assessment by ultrasound is a useful and accurate method to predict the initiation of NIV earlier in patients with ALS.